Role of Sphingolipids in Cardiac Ischemia

鞘脂在心脏缺血中的作用

• 批准号: 6735268
• 负责人: Roger A Sabbadini
• 金额: $ 15.26万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735268
• 关键词: biological signal transduction; cell death; cytoprotection; drug discovery /isolation; drug screening /evaluation; enzyme activity; enzyme induction /repression; enzyme inhibitors; genetically modified animals; genotype; heart disorder chemotherapy; heart disorder diagnosis; heart function; heart ventricle; laboratory mouse; method development; myocardial ischemia /hypoxia; nonhuman therapy evaluation; polymerase chain reaction; protein isoforms; reperfusion; small molecule; sphingolipids; sphingomyelin phosphodiesterase; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Acute cardiac ischemia such as myocardial infarction (MI) is one of the leading causes of death in the US. To date, there are no FDA-approved drugs that reduce the size of the infarct or prevent the progression to MI by directly interfering with the cell death process. Most treatments involve either medical (e.g., TPA) or procedural (e.g., angioplasty) treatments intended to reperfuse the ischemic myocardium. Evidence suggets that a very early event in the cell death process involves activation of sphingolipid signaling molecules that are largely damaging to cardiac cells. It is the goal of the proposed work in both Phase I and Phase II of this SBIR is to prove the principle that the neutral form of sphingomyelinase (nSMase) and its adaptor protein, FAN (factor associated with neutral SMase activation), are valid targets for cardioprotective therapy in patients with myocardial ischemia.These signaling components are up-stream of the MAP kinases, caspases and proto-onogenes of the death process. In addition to validating the targets, we intend to elucidate the mechanisms of action of key sphingolipid signaling molecules in producing the negative inotropy and cell death associated with acute cardiac ischemia. In Phase I of the work, we intend to surgically produce reversible cardiac infarcts in FAN and nSMase knockout mice lacking these important components of the sphingolipid signaling system. In this model of ischemia/reperfusion (IR) injury, infarct sizes as a percentage of areas of risk are expected to be reduced if the FAN/nSMase signaling system is non-functional in the KO mouse compared to control litermates. These methods will be used in conjunction with our cardiomyocyte cell culture model of IR injury provide additional proof-of-principle that the FAN/SMase signaling system is key causal factor in acute cardiac ischemia

描述（由申请人提供）：急性心肌缺血，例如心肌梗塞（MI）是美国的主要原因之一。迄今为止，尚无 FDA 批准的药物可以通过直接干扰细胞死亡过程来缩小梗塞范围或预防心肌梗塞的进展。大多数治疗涉及药物治疗（例如 TPA）或手术治疗（例如血管成形术），旨在对缺血的心肌进行再灌注。有证据表明，细胞死亡过程中的一个非常早期的事件涉及鞘脂信号分子的激活，这对心肌细胞有很大的损害。本次 SBIR 第一期和第二期拟议工作的目标是证明中性形式的鞘磷脂酶 (nSMase) 及其接头蛋白 FAN（与中性 SMase 激活相关的因子）是心肌缺血患者心脏保护治疗的有效靶点。这些信号传导成分位于 MAP 激酶、半胱天冬酶和 死亡过程的原癌基因。除了验证目标之外，我们还打算阐明关键鞘脂信号分子在产生与急性心肌缺血相关的负性肌力和细胞死亡方面的作用机制。在第一阶段的工作中，我们打算通过手术在缺乏鞘脂信号系统重要组成部分的 FAN 和 nSMase 基因敲除小鼠中产生可逆性心肌梗塞。在这种缺血/再灌注（IR）损伤模型中，如果与对照同窝小鼠相比，KO 小鼠中的 FAN/nSMase 信号系统不起作用，则梗死面积占风险区域的百分比预计会减少。这些方法将与我们的 IR 损伤心肌细胞培养模型结合使用，提供额外的原理证明，证明 FAN/SMase 信号系统是急性心肌缺血的关键致病因素